Advertisement

Modeling the Outcome of Systematic TPMT Genotyping or Phenotyping Before Azathioprine Prescription: A Cost-Effectiveness Analysis

  • Kevin Zarca
  • Isabelle Durand-Zaleski
  • Marie-Anne Loriot
  • Gilles Chatellier
  • Nicolas PalletEmail author
Original Research Article

Abstract

Background

Thiopurine S-methyltransferase (TPMT) testing, either by genotyping or phenotyping, can reduce the incidence of adverse severe myelotoxicity episodes induced by azathioprine. The comparative cost-effectiveness of TPMT genotyping and phenotyping are not known.

Objective

Our aim was to assess the cost-effectiveness of phenotyping-based dosing of TPMT activity, genotyping-based screening and no screening (reference) for patients treated with azathioprine.

Methods

A decision tree was built to compare the conventional weight-based dosing strategy with phenotyping and with genotyping using a micro-simulation model of patients with inflammatory bowel disease from the perspective of the French health care system. The time horizon was set up as 1 year. Only direct medical costs were used. Data used were obtained from previous reports, except for screening test and admission costs, which were from real cases. The main outcome was the cost-effectiveness ratios, with an effectiveness criterion of one averted severe myelotoxicity episode.

Results

The total expected cost of the no screening strategy was €409/patient, the total expected cost of the phenotyping strategy was €427/patient, and the total expected cost of the genotyping strategy was €476/patient. The incremental cost-effectiveness ratio was €2602/severe myelotoxicity averted in using the phenotyping strategy, and €11,244/severe myelotoxicity averted in the genotyping strategy compared to the no screening strategy. At prevalence rates of severe myelotoxicity > 1%, phenotyping dominated genotyping and conventional strategies.

Conclusion

The phenotype-based strategy to screen for TPMT deficiency dominates (cheaper and more effective) the genotype-based screening strategy in France. Phenotype-based screening dominates no screening in populations with a prevalence of severe myelosuppression due to azathioprine of > 1%.

Notes

Compliance with Ethical Standards

Funding

No funding to declare.

Conflict of interest

The authors (KV, IDZ, MAL, GC and NP) declare that they have no competing interests.

Ethical approval and informed consent

This study did not involve human subjects.

References

  1. 1.
    Chouchana L, Narjoz C, Beaune P, Loriot M-A, Roblin X. Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2012;35:15–36.CrossRefGoogle Scholar
  2. 2.
    Allison AC. Immunosuppressive drugs: the first 50 years and a glance forward. Immunopharmacology. 2000;47:63–83.CrossRefGoogle Scholar
  3. 3.
    Halloran PF. Immunosuppressive drugs for kidney transplantation. NEJM. 2004;351:2715–29.CrossRefGoogle Scholar
  4. 4.
    Petit E, Langouet S, Akhdar H, Nicolas-Nicolaz C, Guillouzo A, Morel F. Differential toxic effects of azathioprine, 6-mercaptopurine and 6-thioguanine on human hepatocytes. Toxicol In Vitro. 2007;22:632–42.CrossRefGoogle Scholar
  5. 5.
    Karran P, Attard N. Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nat Rev Cancer. 2008;8:24–36.CrossRefGoogle Scholar
  6. 6.
    Taylor AL, Watson CJ, Bradley JA. Immunosuppressive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol. 2005;56:23–46.CrossRefGoogle Scholar
  7. 7.
    Stet EH, Abreu RAD, Janssen YP, Bökkerink JP, Trijbels FJ. A biochemical basis for synergism of 6-mercaptopurine and mycophenolic acid in Molt F4, a human malignant T-lymphoblastic cell line. Biochem Biophys Acta. 1993;1180:277–82.Google Scholar
  8. 8.
    Huang H-Y, Chang H-F, Tsai M-J, Chen J-S, Wang M-J. 6-mercaptopurine attenuates tumor necrosis factor-α production in microglia through Nur77-mediated transrepression and PI3K/Akt/mTOR signaling-mediated translational regulation. J Neuroinflamm. 2016;13(78):1–20.Google Scholar
  9. 9.
    Zochowska D, Zegarska J, Hryniewiecka E, Samborowska E, Jazwiec R, Tszyrsznic W, et al. Determination of concentrations of azathioprine metabolites 6-thioguanine and 6-methylmercaptopurine in whole blood with the use of liquid chromatography combined with mass spectrometry. Transplant Proc. 2016;48:1836–9.CrossRefGoogle Scholar
  10. 10.
    Moriyama T, Nishii R, Perez-Andreu V, Yang W, Klussmann F-A, Zhao X, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet. 2016;48:367–73.CrossRefGoogle Scholar
  11. 11.
    Ansari A, Hassan C, Duley J, Marinaki A, Shobowale-Bakre EM, Seed P, et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther. 2002;16(10):1743–50.CrossRefGoogle Scholar
  12. 12.
    Gardiner SJ, Begg EJ. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev. 2006;58(3):521–90.CrossRefGoogle Scholar
  13. 13.
    Gardiner SJ, Gearry RB, Barclay ML, Begg EJ. Two cases of thiopurine methyltransferase (TPMT) deficiency—a lucky save and a near miss with azathioprine. Br J Clin Pharmacol. 2006;62(4):473–6.CrossRefGoogle Scholar
  14. 14.
    Priest VL, Begg EJ, Gardiner SJ, Frampton CM, Gearry RB, Barclay ML, et al. Pharmacoeconomic analyses of azathioprine, methotrexate and prospective pharmacogenetic testing for the management of inflammatory bowel disease. Pharmacoeconomics. 2006;24(8):767–81.CrossRefGoogle Scholar
  15. 15.
    Gisbert JP, Gomollon F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am J Gastroenterol. 2008;103(7):1783–800.CrossRefGoogle Scholar
  16. 16.
    Krynetski EY, Evans WE. Genetic polymorphism of thiopurine S-methyltransferase: molecular mechanisms and clinical importance. Pharmacology. 2000;61(3):136–46.CrossRefGoogle Scholar
  17. 17.
    McLeod HL, Krynetski EY, Relling MV, Evans WE. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia. 2000;14(4):567–72.CrossRefGoogle Scholar
  18. 18.
    Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut. 1993;34(8):1081–5.CrossRefGoogle Scholar
  19. 19.
    Bergan S, Bentdal O, Sodal G, Brun A, Rugstad HE, Stokke O. Patterns of azathioprine metabolites in neutrophils, lymphocytes, reticulocytes, and erythrocytes: relevance to toxicity and monitoring in recipients of renal allografts. Ther Drug Monit. 1997;19(5):502–9.CrossRefGoogle Scholar
  20. 20.
    Schwab M, Schaffeler E, Marx C, Fischer C, Lang T, Behrens C, et al. Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease: impact of thiopurine S-methyltransferase polymorphism. Pharmacogenetics. 2002;12(6):429–36.CrossRefGoogle Scholar
  21. 21.
    Jeurissen ME, Boerbooms AM, van de Putte LB. Pancytopenia related to azathioprine in rheumatoid arthritis. Ann Rheum Dis. 1988;47(6):503–5.CrossRefGoogle Scholar
  22. 22.
    Zelinkova Z, Derijks LJ, Stokkers PC, Vogels EW, van Kampen AH, Curvers WL, et al. Inosine triphosphate pyrophosphatase and thiopurine S-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Clin Gastroenterol Hepatol. 2006;4(1):44–9.CrossRefGoogle Scholar
  23. 23.
    Hartford C, Vasquez E, Schwab M, Edick MJ, Rehg JE, Grosveld G, et al. Differential effects of targeted disruption of thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics. Cancer Res. 2007;67(10):4965–72.CrossRefGoogle Scholar
  24. 24.
    Dewit O, Moreels T, Baert F, Peeters H, Reenaers C, de Vos M, et al. Limitations of extensive TPMT genotyping in the management of azathioprine-induced myelosuppression in IBD patients. Clin Biochem. 2011;44(13):1062–6.CrossRefGoogle Scholar
  25. 25.
    Colombel JF, Ferrari N, Debuysere H, Marteau P, Gendre JP, Bonaz B, et al. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy. Gastroenterology. 2000;118(6):1025–30.CrossRefGoogle Scholar
  26. 26.
    Chouchana L, Narjoz C, Roche D, Golmard JL, Pineau B, Chatellier G, et al. Interindividual variability in TPMT enzyme activity: 10 years of experience with thiopurine pharmacogenetics and therapeutic drug monitoring. Pharmacogenomics. 2014;15(6):745–57.CrossRefGoogle Scholar
  27. 27.
    Szumlanski CL, Honchel R, Scott MC, Weinshilboum RM. Human liver thiopurine methyltransferase pharmacogenetics: biochemical properties, liver-erythrocyte correlation and presence of isozymes. Pharmacogenetics. 1992;2(4):148–59.CrossRefGoogle Scholar
  28. 28.
    Ganiere-Monteil C, Medard Y, Lejus C, Bruneau B, Pineau A, Fenneteau O, et al. Phenotype and genotype for thiopurine methyltransferase activity in the French Caucasian population: impact of age. Eur J Clin Pharmacol. 2004;60(2):89–96.CrossRefGoogle Scholar
  29. 29.
    Hindorf U, Peterson C, Almer S. Assessment of thiopurine methyltransferase and metabolite formation during thiopurine therapy: results from a large Swedish patient population. Ther Drug Monit. 2004;26(6):673–8.CrossRefGoogle Scholar
  30. 30.
    Krijkamp EM, Alarid-Escudero F, Enns EA, Jalal HJ, Hunink MGM, Pechlivanoglou P. Microsimulation modeling for health decision sciences using R: a tutorial. Med Decis Mak. 2018;38(3):400–22.CrossRefGoogle Scholar
  31. 31.
    Serpe L, Calvo PL, Muntoni E, D’Antico S, Giaccone M, Avagnina A, et al. Thiopurine S-methyltransferase pharmacogenetics in a large-scale healthy Italian-Caucasian population: differences in enzyme activity. Pharmacogenomics. 2009;10(11):1753–65.CrossRefGoogle Scholar
  32. 32.
    Lennard L, Cartwright CS, Wade R, Richards SM, Vora A. Thiopurine methyltransferase genotype-phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia. Br J Clin Pharmacol. 2013;76(1):125–36.CrossRefGoogle Scholar
  33. 33.
    Milek M, Karas Kuzelicki N, Smid A, Mlinaric-Rascan I. S-adenosylmethionine regulates thiopurine methyltransferase activity and decreases 6-mercaptopurine cytotoxicity in MOLT lymphoblasts. Biochem Pharmacol. 2009;77(12):1845–53.CrossRefGoogle Scholar
  34. 34.
    Mircheva J, Legendre C, Soria-Royer C, Thervet E, Beaune P, Kreis H. Monitoring of azathioprine-induced immunosuppression with thiopurine methyltransferase activity in kidney transplant recipients. Transplantation. 1995;60(7):639–42.CrossRefGoogle Scholar
  35. 35.
    Schaeffeler E, Fischer C, Brockmeier D, Wernet D, Moerike K, Eichelbaum M, et al. Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics. 2004;14(7):407–17.CrossRefGoogle Scholar
  36. 36.
    Kirchgesner J, Lemaitre M, Rudnichi A, Racine A, Zureik M, Carbonnel F, et al. Therapeutic management of inflammatory bowel disease in real-life practice in the current era of anti-TNF agents: analysis of the French administrative health databases 2009–2014. Aliment Pharmacol Ther. 2017;45(1):37–49.CrossRefGoogle Scholar
  37. 37.
    Roblin X, Oussalah A, Chevaux JB, Sparrow M, Peyrin-Biroulet L. Use of thiopurine testing in the management of inflammatory bowel diseases in clinical practice: a worldwide survey of experts. Inflamm Bowel Dis. 2011;17(12):2480–7.CrossRefGoogle Scholar
  38. 38.
    Oh KT, Anis AH, Bae SC. Pharmacoeconomic analysis of thiopurine methyltransferase polymorphism screening by polymerase chain reaction for treatment with azathioprine in Korea. Rheumatology (Oxford). 2004;43(2):156–63.CrossRefGoogle Scholar
  39. 39.
    Winter J, Walker A, Shapiro D, Gaffney D, Spooner RJ, Mills PR. Cost-effectiveness of thiopurine methyltransferase genotype screening in patients about to commence azathioprine therapy for treatment of inflammatory bowel disease. Aliment Pharmacol Ther. 2004;20(6):593–9.CrossRefGoogle Scholar
  40. 40.
    Dubinsky MC, Reyes E, Ofman J, Chiou CF, Wade S, Sandborn WJ. A cost-effectiveness analysis of alternative disease management strategies in patients with Crohn’s disease treated with azathioprine or 6-mercaptopurine. Am J Gastroenterol. 2005;100(10):2239–47.CrossRefGoogle Scholar
  41. 41.
    van den Akker-van Marle ME, Gurwitz D, Detmar SB, Enzing CM, Hopkins MM, Gutierrez de Mesa E, et al. Cost-effectiveness of pharmacogenomics in clinical practice: a case study of thiopurine methyltransferase genotyping in acute lymphoblastic leukemia in Europe. Pharmacogenomics. 2006;7(5):783–92.CrossRefGoogle Scholar
  42. 42.
    Hagaman JT, Kinder BW, Eckman MH. Thiopurine S-methyltransferase [corrected] testing in idiopathic pulmonary fibrosis: a pharmacogenetic cost-effectiveness analysis. Lung. 2010;188(2):125–32.CrossRefGoogle Scholar
  43. 43.
    Thompson AJ, Newman WG, Elliott RA, Roberts SA, Tricker K, Payne K. The cost-effectiveness of a pharmacogenetic test: a trial-based evaluation of TPMT genotyping for azathioprine. Value Health. 2014;17(1):22–33.CrossRefGoogle Scholar
  44. 44.
    Husereau D, Drummond M, Petrou S, Carswell C, Moher D, Greenberg D, et al. Consolidated health economic evaluation reporting standards (CHEERS) statement. BMJ. 2013;346:f1049.CrossRefGoogle Scholar
  45. 45.
    Newman WG, Payne K, Tricker K, Roberts SA, Fargher E, Pushpakom S, et al. A pragmatic randomized controlled trial of thiopurine methyltransferase genotyping prior to azathioprine treatment: the TARGET study. Pharmacogenomics. 2011;12(6):815–26.CrossRefGoogle Scholar
  46. 46.
    Anglicheau D, Sanquer S, Loriot MA, Beaune P, Thervet E. Thiopurine methyltransferase activity: new conditions for reversed-phase high-performance liquid chromatographic assay without extraction and genotypic-phenotypic correlation. J Chromatogr B. 2002;773(2):119–27.CrossRefGoogle Scholar
  47. 47.
    Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst. 1999;91(23):2001–8.CrossRefGoogle Scholar
  48. 48.
    Naughton MA, Battaglia E, O’Brien S, Walport MJ, Botto M. Identification of thiopurine methyltransferase (TPMT) polymorphisms cannot predict myelosuppression in systemic lupus erythematosus patients taking azathioprine. Rheumatology (Oxford). 1999;38(7):640–4.CrossRefGoogle Scholar
  49. 49.
    Ishioka S, Hiyama K, Sato H, Yamanishi Y, McLeod HL, Kumagai K, et al. Thiopurine methyltransferase genotype and the toxicity of azathioprine in Japanese. Intern Med. 1999;38(12):944–7.CrossRefGoogle Scholar
  50. 50.
    Gisbert JP, Luna M, Mate J, Gonzalez-Guijarro L, Cara C, Pajares JM. Choice of azathioprine or 6-mercaptopurine dose based on thiopurine methyltransferase (TPMT) activity to avoid myelosuppression. A prospective study. Hepatogastroenterology. 2006;53(69):399–404.Google Scholar
  51. 51.
    Briggs A, Sculpher M, Claxton K. Decision modelling for health economic evaluation. Oxford: Oxford University Press; 2006.Google Scholar
  52. 52.
    Verbelen M, Weale ME, Lewis CM. Cost-effectiveness of pharmacogenetic-guided treatment: are we there yet? Pharmacogenomics J. 2017;17(5):395–402.CrossRefGoogle Scholar
  53. 53.
    Lennard L. Implementation of TPMT testing. Br J Clin Pharmacol. 2014;77(4):704–14.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Kevin Zarca
    • 1
    • 2
  • Isabelle Durand-Zaleski
    • 1
    • 2
  • Marie-Anne Loriot
    • 3
    • 4
  • Gilles Chatellier
    • 4
    • 5
    • 6
  • Nicolas Pallet
    • 3
    • 4
    Email author
  1. 1.Assistance Publique-Hôpitaux de Paris, DRCI-URC Eco Ile-de-France (AP-HP)ParisFrance
  2. 2.Assistance Publique-Hôpitaux de Paris, service de santé publique, Henri Mondor-Albert-ChenevierCréteilFrance
  3. 3.Service de BiochimieHôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Université Paris DescatesParisFrance
  4. 4.Université Paris Descartes, Sorbonne Paris CitéParisFrance
  5. 5.Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Unité de Recherche CliniqueParisFrance
  6. 6.Centre d’Investigation Clinique 1418 (CIC1418)ParisFrance

Personalised recommendations